Burns and wounds are often colonized with highly infectious pathogens that are often resistant to antibiotics. The product underdevelopment contains a low concentration of the active ingredient, D2A21, which is a 23 amino-acid amphipathic peptide. D2A21 is active against many infectious agents, including multidrug-resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus. Also, anti-fungal activity has been demonstrated against Candida albicans, Aspergillus niger, Mucor sp, and Trichophyton mentagrophytes.
D2A21 does not inhibit wound healing and is not cytotoxic to cultured keratinocyte skin cells. It is not a dermal irritant, nor does it induce contact sensitization. The peptide is not a mammalian or bacterial mutagen. Acute and chronic systemic toxicity studies have established a safe dose, which is a multiple of the efficacious dose.
In vitro data have shown that Pseudomonas aeruginosa cells are killed within 30 minutes, and Staphylococcus aureus cells are killed within 2 hours. No growth of either species was detected at 24 hours after incubation with the peptides. These results have been confirmed in two animal infectivity models. In a standard infected in vivo rodent burn model, D2A21 demonstrated significant antibacterial activity against Pseudomonas aeruginosa, sterilizing burn eschar and decreasing sub-eschar bacterial load, allowing for a markedly significant improvement in survival in this infected burn wound model. The model was employed to evaluate the effects of D2A21 on eschar and subeschar muscle quantitative cultures against Pseudomonas aeruginosa. By day 3 (three) there was a four-fold decrease in subeschar bacterial growth and zero eschar bacterial growth in the D2A21 treated group versus the control group, which had 9.5 x 107 eschar colony forming units. In this same model, D2A21 demonstrated significant improvement in percent survival (85% versus 0% in the control group, p < 0.001).
A second model was employed to demonstrate the in vivo efficacy in a standard infected wound model. This study compared D2A21 to the standards of care; silver sulfadiazine (SSD) and Sulfamylon. Forty-eight (48) rodents with full thickness dorsum defects were treated with either D2A21, SSD, Sulfamylon, or control gel daily for 20 days. Percent survival was 100% for the DaA21 group, 83% for the Sulfamylon group, 50% for control and 33% for SSD treated animals. These results demonstrate that D2A21 is better than or at least equal to the current standards of care for the treatment of infected wounds.
The use of topical antimicrobial agents has been an important adjunct in the prevention and treatment of burn/wound infections. However, there are several disadvantages to the use of the most common agents, silver sulfadiazine (SSD) and mafenide acetate (the active ingredient in Sulfamylon), including their substantial ability to inhibit wound healing when applied at clinically effective antimicrobial dosages. In addition, both of these agents are particularly cytotoxic to cultured keratinocyte skin grafts, a procedure used commonly in severely burned patients. Furthermore, the development of multi-drug resistant pathogens in the hospital setting has become an increasingly important problem in the management of major surgical infections, including those due to burn wounds. Burn wound sepsis remains the most common and serious complication of major burn injury, accounting for over 60% of deaths in burn patients today. Therefore, there is an unmet medical need for novel agents to provide local control of infection, in particular for drug resistant organisms, without inhibiting normal tissue repair processes. Such agents could have widespread applicability in the management of burn and wound patients in both hospital and out-patient settings.